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1 Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas, United States
2 Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States
3 Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, United States
4 Cancer Biology, Universty of Texas MD Anderson Cancer Center, Houston, Texas, United States
* To whom correspondence should be addressed. E-mail: clogsdon{at}mdanderson.org.
Background & Aims: Endoplasmic reticulum stress mechanisms have been found to play critical roles in a number of diseases states, such as diabetes mellitus and Alzheimer`s but whether they are involved in acute pancreatitis is unknown. Here we show for the first time that all major ER stress sensing and signalling mechanisms are present in exocrine acini and are activated early in the arginine model of experimental acute pancreatitis. Methods: Pancreatitis was induced in rats by ip injection of 4.0g/kg bw arginine. Pancreatitis severity was assessed by analysis of serum amylase, pancreatic trypsin activity, water content and histology. ER stress related molecules PERK, eIF2
, ATF6, XBP-1, BiP, CHOP and caspase 12 were analyzed. Results: Arginine treatment induced rapid and severe pancreatitis, as indicated by increased serum amylase, pancreatic tissue edema, and acinar cell damage within 4 h. Arginine treatment also caused an early activation of ER stress, as indicated by phosphorylation of PERK and its downstream target eIF2 and ATF6 translocation into the nucleus (within 1 h) and up-regulation of BiP (within 4h). XBP-1 splicing and CHOP expression were observed within 8 h. After 24 h, increased activation of the ER stress related pro-apoptotic molecule caspase 12 was observed along with an increase in caspase 3 activity and TUNEL staining in exocrine acini. Conclusions: These results indicate that ER stress is an important early acinar cell event that likely contributes to the development of acute pancreatitis in the arginine model.
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